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Journal of Virology, December 2007, p. 12889-12898, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01563-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Orally Administered Amyloidophilic Compound Is Effective in Prolonging the Incubation Periods of Animals Cerebrally Infected with Prion Diseases in a Prion Strain-Dependent Manner{triangledown}

Yuri Kawasaki,1 Keiichi Kawagoe,2 Chun-jen Chen,2 Kenta Teruya,1 Yuji Sakasegawa,1 and Katsumi Doh-ura1*

Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai, Japan,1 Tokyo R & D Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan2

Received 18 July 2007/ Accepted 4 September 2007

The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain-dependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that diglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.

* Corresponding author. Mailing address: Department of Prion Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Phone: 81-22-717-8232. Fax: 81-22-717-7656. E-mail: doh-ura{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 19 September 2007.

Journal of Virology, December 2007, p. 12889-12898, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01563-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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